Adenylyl cyclase type VI corrects cardiac sarcoplasmic reticulum calcium uptake defects in cardiomyopathy

Tang, Tong; Gao, Mei Hua; Roth, David M.; Guo, Tracy; Hammond, H. Kirk

doi:10.1152/ajpheart.00356.2004

Cited by 40 publications

(43 citation statements)

References 43 publications

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“…Both defective calcium uptake by SERCA2a and defective calcium release through the SR calcium release channel ryanodine receptor 2 (RyR2) occur in clinical and animal models of heart failure. 9,15,16 In the present study, we found that AC VI expression was associated with increased SERCA2a affinity for calcium ( Figures 7C and 7D). This improvement of calcium uptake by AC VI was associated with increased phosphorylation of phospholamban at Ser16; protein contents of phospholamban and SERCA2a were unchanged ( Figures 7A and 7B).…”

Section: Discussionsupporting

confidence: 64%

Increased Cardiac Adenylyl Cyclase Expression Is Associated With Increased Survival After Myocardial Infarction

et al. 2006

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Section: Discussionsupporting

confidence: 64%

Increased Cardiac Adenylyl Cyclase Expression Is Associated With Increased Survival After Myocardial Infarction

et al. 2006

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“…Again, this study is based on extensive preclinical data showing that increasing adenylyl cyclase VI activity would increase cAMP levels and, hence, SERCA activity and contractility in experimental heart failure. 24 …”

Section: Restoration Of Serca As a Therapeutic Strategymentioning

confidence: 99%

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Eisner

Caldwell

Trafford

2013

Circulation Research

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T his article reflects on the impact of a classic paper identifying the effects of loss of sarcoplasmic reticulum Ca-ATPase activity in heart failure. The Classic ArticleUnderstanding the effects of heart failure on contraction and Ca signaling in the heart has long been a priority. By the late 1980s, many studies on animal models had shown that heart failure resulted in a slowing of the decay of the systolic Ca transient 1 because of a decrease in the expression of the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA).2 Work using human tissue found similar changes.3,4 In 1994, Hasenfuss et al 5 published a now classic article in Circulation Research entitled "Relation between myocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and non-failing human myocardium." Previous work had shown that SERCA expression and activity were decreased in heart failure. Other work had shown that the increase of force seen on increasing the frequency of stimulation (the positive forcefrequency curve) disappeared in heart failure. Hasenfuss et al 5 showed that the degree of change in the force-frequency relationship correlated with the loss of SERCA. Hearts with low levels of SERCA developed maximum force at lower frequencies than those with higher levels. In addition, and suggested as causative of the reduced force-frequency responses, the failing hearts had reduced SERCA-mediated Ca uptake.The work in this article has influenced 2 areas of research: changes of SR function in heart failure and restoration of SERCA as a therapeutic strategy. We consider these in turn. SR Function in Heart FailureTwenty years later, the role of changes of SERCA expression in heart failure is well-established. The majority of studies of heart failure in either humans or experimental animals show that SERCA activity is decreased in heart failure. This decrease of SERCA has 2 immediate effects on Ca signaling. First, it slows the rate of decay of the systolic Ca transient, thereby impairing relaxation. Second, as a consequence of decreasing SR Ca content, it will decrease the amplitude of the systolic Ca transient and thus contraction. However, subsequent work has shown that changes of SERCA are part of a group of changes of Ca signaling that occur in heart failure. As highlighted in Figure, 2 other factors will also decrease the SR Ca content. First, there is an increase of NCX expression or activity. [6][7][8] This adaptation has the benefit of making up for the reduced SERCA, thereby preserving relaxation. In a subsequent article, Hasenfuss et al 9 showed that patients with increased NCX had better diastolic function than did those with lower NCX. However, although increased NCX improves diastolic function, it will decrease SR Ca content and thereby depress systolic function further. Second, many studies have now shown that the open probability of the RyR is increased in heart failure. [10][11][12] This may occur as a result of phosphorylation, 10 hyponitrosylation, 13 or oxidation. 14 This increased opening will lead to a...

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“…11,17 Additional experiments to measure cAMP production were also performed with myocardial homogenates from neonatal mice (1 day Activities of intrinsic protein kinase A (PKA) and protein phosphatases 1 (PP1) and 2A (PP2A) were measured as described previously. 11,16 Western blotting was performed as described previously. 16 Additional experiments were conducted with LV samples from isolated hearts perfused with dobutamine (10 mol/L, 5 minutes).…”

Section: ؉mentioning

confidence: 99%

“…11,16 Western blotting was performed as described previously. 16 Additional experiments were conducted with LV samples from isolated hearts perfused with dobutamine (10 mol/L, 5 minutes).…”

Section: ؉mentioning

confidence: 99%

Adenylyl Cyclase Type 6 Deletion Decreases Left Ventricular Function via Impaired Calcium Handling

et al. 2008

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Background-Adenylyl cyclases (ACs) are a family of effector molecules for G-protein-coupled receptors. The 2 ACs most abundantly expressed in cardiac myocytes are types 5 (AC5) and 6 (AC6), which have 65% amino acid homology. It has been speculated that coexpression of 2 AC types in cardiac myocytes represents redundancy, but the specific role of AC6 in cardiac physiology and its differences from AC5 remain to be defined. Methods and Results-We generated transgenic mice with targeted deletion of AC6. Deletion of AC6 was associated with reduced left ventricular contractile function (Pϭ0.026) and relaxation (Pϭ0.041). The absence of AC6 was associated with a 48% decay in ␤-adrenergic receptor-stimulated cAMP production in cardiac myocytes (Pϭ0.003) and reduced protein kinase A activity (Pϭ0.015). In addition, phospholamban phosphorylation was reduced (Pϭ0.015), sarcoplasmic reticulum Ca 2ϩ -ATPase activity was impaired (PϽ0.0001), and cardiac myocytes showed marked abnormalities in calcium transient formation (Pϭ0.001). Conclusions-The

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Adenylyl cyclase type VI corrects cardiac sarcoplasmic reticulum calcium uptake defects in cardiomyopathy

Cited by 40 publications

References 43 publications

Increased Cardiac Adenylyl Cyclase Expression Is Associated With Increased Survival After Myocardial Infarction

Increased Cardiac Adenylyl Cyclase Expression Is Associated With Increased Survival After Myocardial Infarction

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Adenylyl Cyclase Type 6 Deletion Decreases Left Ventricular Function via Impaired Calcium Handling

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